NF-κB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes

NF-κB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes

Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, and Molecular Biology Institute, University of California, Los Angeles, CA 90095

Communicated by Lutz Birnbaumer, University of California, Los Angeles, CA (received for review May 6, 1999)

Abstract

Activation of CD40 is essential for thymus-dependent humoral immune responses and rescuing B cells from apoptosis. Many of the effects of CD40 are believed to be achieved through altered gene expression. In addition to Bcl-x, a known CD40-regulated antiapoptotic molecule, we identified a related antiapoptotic molecule, A1/Bfl-1, as a CD40-inducible gene. Inhibition of the NF-κB pathway by overexpression of a dominant-active inhibitor of NF-κB abolished CD40-induced up-regulation of both the Bfl-1 and Bcl-x genes and also eliminated the ability of CD40 to rescue Fas-induced cell death. Within the upstream promoter region of Bcl-x, a potential NF-κB-binding sequence was found to support NF-κB-dependent transcriptional activation. Furthermore, expression of physiological levels of Bcl-x protected B cells from Fas-mediated apoptosis in the absence of NF-κB signaling. Thus, our results suggest that CD40-mediated cell survival proceeds through NF-κB-dependent up-regulation of Bcl-2 family members.

Footnotes

↵ * H.H.L. and H.D. contributed equally to this work.
↵ † To whom reprint requests should be addressed. E-mail: genhongc{at}microbio.ucla.edu.
ABBREVIATIONS:

IκB,

inhibitor of NF-κB;

TNF,

tumor necrosis factor;

TRAF,

TNF receptor-associated factor;

HA,

hemagglutinin;

4-OHT,

4-hydroxytamoxifen;

ER,

estrogen receptor ligand-binding domain;

sIgM,

surface IgM